The challenges of genetically diagnosing complex I deficiency, the most common cause of childhood-onset mitochondrial disease, are not only due to the very broad spectrum of clinical presentations, but also because of the large number of potential disease-causing genes.
This review discusses the structure and function of complex I in light of recent X-ray crystallographic findings; the currently accepted model of complex I assembly; clinical phenotypes and genetic causes of complex I deficiency; genotype:phenotype correlations informed by a systematic review of all 172 patients with nuclear-encoded complex I deficiency reported to date; mouse models; and approaches to treatment.
Timely diagnosis can be extremely challenging, but has considerable implications in terms of treatment and genetic counselling. Clinical and radiological clues to diagnosis are highlighted, together with genotype:phenotype correlations where they exist, and a diagnostic flowchart is presented which may facilitate more rapid diagnosis of future cases. (By Shamima Rahman FRCP FRCPCH PhD, http://jmg.bmj.com/content/49/9/578 )